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    SINO-EUROPE SYMPOSIUM ON TRADITIONAL CHINESE MEDICINE & HERBAL MEDICINE-MARKET OVERVIEW ®ULATION POLICY

    2019-12-21 14:44:45ChinaExperienceandChallengesinEURegistrationandDeclarationZhangShunnan章順楠
    關鍵詞:參考文獻

    China's Experience and Challenges in EU Registration and Declaration Zhang Shunnan (章順楠)

    (Research Professor, Vice General Manager, Tasly Pharmaceutical Group Co., Ltd., China)

    Hello everyone, I would like to share with you the declaration of the phytomedicine produced by Tasly.

    There are three parts: The first is the company introduction. It is hoped that Chinese companies and European companies, can have further cooperation opportunities. Next, I will give a brief introduction to our company.

    Tasly Pharmaceutical Group Co., Ltd. was founded in 1994 and listed on the Shanghai Stock Exchange in 2002. It is one of the top 10 enterprises in China's pharmaceutical industry. Traditional Chinese medicine is our major products. Of course, pharmaceutical chemicals and biological medicines are also included. We are mainly engaged in the modernization and internationalization of traditional Chinese medicine. Last year, our entire sales revenue has exceeded 16 billion Yuan.

    In addition, the parent company of Tasly Pharmaceutical Group is our holding group. Tasly Holding Group is mainly based on the great health industry.In the morning, some experts mentioned that there is inseparable relationship between Chinese medicine and enlarged health. In addition to biomedical industry, we also have medical rehabilitation, health regime and health management industries. In our entire layout in China, Tianjin is our headquarter, with Chinese medicine R & D and production. From southwestern China to the northwest,we have our corresponding medicine plant base. The pharmaceutical chemicals are mainly in Jiangsu, and then the biopharmaceuticals are in Shanghai. We also have our service in corporate rehabilitation, medical care, children's education etc. Moreover, there are Guotai wine in Guizhou, and Deepure water in the northeast. In the international layout, the international research and development of new medicines, is mainly based in US,headquartered in Maryland, USA. Compound Danshen Dripping Pills that we are currently developing is in phase III as the 1st cardiovascular botanic drug applying for NDA of FDA. The clinic has been completed, and now has been undergoing the confirmatory phase III.

    There are two parts in Europe. One is the traditional Chinese medicine sales in Netherlands, and the other is a German company in Hannover, which mainly to explore a treatment model combining Chinese and Western medicine, by cooperating with Hannover Medical University.

    Additionally, we have Kangping Medical cooperation in Australia, which mainly explores another model: general treatment + Chinese medicine rehabilitation. That is the whole business expansion that has been carried out so far in the internationalization of Chinese medicine.

    Our products are mainly traditional Chinese medicine products, which now include 13 Tasly main prouducts of more than 100 million. Compound Danshen Dripping Pill is the highest sales of oral Chinese patent medicines in China so far, close to 4 billion Yuan per year. Yangxue Qingnao Granules are our second largest product of Chinese patent medicines, and now its annual sale is close to one billion. We also have pharmaceutical chemicals. The top one is Temozolomide capsule named Diqing, which is effective to anti-glioma and metastasis. Besides the oral medicines, we also have TCM and biomedicine frozen powder for injection. The Pro-UK, which is a human reorganization recombinant thrombolytic agent. Generally, the treatment window period of cerebral infroction or myocardial infarction,is in 4.5 hour, fortunately the Pro-UK has the same significant clinical effectiveness during 4.5 to 6 hours.The whole window of thrombolytic treatment has been extended. This is the only first class new medicine in China during the 11thFive-Year Plan period.

    In the 2ndpart, I will report mainly about the registration of our E01 Danshen Capsule in the Netherlands. There are many colleagues today, all of whom are from internationalization project team and from capital team. They come to discuss with experts the further cooperation opportunities. Thus I will give you an introduction of the E01 Danshen capsule that we are doing now.

    We started the project at the end of 2011, and the process development in 2012. As it is a single herb prescription medicine, the process development is relatively quick at completing the corresponding process verification. In early 2014, according to the eCTD, we submitted our application, then we finished two cycles of review amendments in 2015. After CTD dossier submitted,CBG came to the site for inspection, and we got the EUGMP in 2014 and MAH certificate in January 2016. After launch, we had two corresponding changes on update storage condition, and passed the inspection again in 2017.

    The approved indication of Danshen Capsule is not the most popular cardiovascular indication nowadays. Instead, it is based on the TUR requirements for indication and the traditional usage of Danshen. We chose an indication for treating dysmenorrhea. This is the product prescription. One capsule contains 325 mg of extract (as dry extract) from the Salvia miltiorrhiza Bunge radix et rhizoma (Danshen), equivalent to 1.5 grams - 2.0 grams of Salvia miltiorrhiza roots.

    Regarding TUR registration, the traditional use evidence should have 15 years of application history in the EU and 30 years outside the EU. Danshen, with its very long history of application, has been collected in Chinese Pharmacopoeia in 1963, which listed the function of Danshen including menstruation and pain relief, and this usage started from ancient China. And it has other indicaitons, according to the same principles of its main function, including treatment of chest discomfort and coronary heart disease. The history of use in Europe is also more than 15 years, which has been initiated in German Pharmacopoeia in 1996, and there are many other relevant literatures, and we have been selling such products in Dutch Tasly Company. For the choice of indications, we choose to improve the blood circulation in the begining, because Danshen is now very popular in activating blood circulation. But finally, for the indication of dysmenorrhea, we consider that there is no deviation in the understanding of the application of the treatment when patience conduct self-diagnosis.

    We do not know whether this indication is feasible or not. There are many components in Danshen. Firstly,we use the theory of traditional Chinese medicine to see if it can really help us understand this product. After it was analyzed, it was found that the whole components can be used to treat dysmenorrhea, because Chinese medicine thinks pain results from stagnation, the main causes are cold coagulation, blood stasis, qi stagnation and wind blockage.

    Accordingly, for Danshen, it has the function of nourishing qi, nourishing blood, regulating menstruation,etc. There has a classic saying that Danshen, as an individual herb, is equivalent the Four-herb Soup, a very famous gynecology Chinese medicine. So in this regard,the mechanism of action is supported. Meanwhile, per modern pharmacology studies, its main components have the functions of smooth muscle relaxation, anti-platelet aggregation, anti-trophy, anti-inflammation, etc. So, it can improve the contraction of uterine smooth muscle and inflammatory reaction. As a result, Danshen can be used to treat dysmenorrhea. Overall, whether Chinese medicine theory or modern pharmacology, it shows that Danshen can be used for the treatment of dysmenorrhea.Of course, the role of menstruation and pain relief were also mentioned in ancient China, thus we established this indication.

    Although TUR does not require clinical research,for it can be summarized with its traditional application history we have also made an internal clinical observation.It was very interesting that we used the international VAS scale and COX scale for evaluation on dysmenorrhea.As the VAS scale exceeded 4 points, it was basically painful. After 9 points or so, it was be overwhelmed with sorrow. According to this situation, patients are required to take Danshen Capsule 4 days before menstruation,3 pills once, twice a day, for 2 weeks, including the menstrual period. The results were very interesting. We did not take the medicine during the baseline period. We had done only an internal observation, in which a total of 18 people signed up. Three of the applicants didn't start the program for they are too busy or pregnancy.And the rest took medication for 3 months. It was not particularly obvious during the first month. After the 2ndmonth, 3 of the colleagues felt that the pain was basically reduced from 5 or 6 points before the original medication,to 0 point. It is amazing to take the medication. It was statistically significant for the other dozens of people taking medications for three months. This is the statistical P value, 0.755 between 1stmonth and baseline, 0.003 between 2ndmonth and baseline. Just imagine, if we compare the Danshen with painkiller tablets, for the treatment of dysmenorrhea, Danshen will not have better effect, but you konw, the patients in this trail have been taking the painkiller every month in the past years, why,the painkiller only relieve the pain, but after taking Danshen for two or three months, there will be no pain in the future, so, this is the advantage for Danshen to treat dysmenorrhea.

    Compound Danshen Dripping Pills are for the treatment of coronary heart disease and angina pectoris,there is an indicator to observe the amount of nitroglycerin used in the FDA NDA clinical study. Data related proved that the amount of nitroglycerin used by the group taking Compound Danshen Dripping Pills gradually decreased,which indicated that the angina was ran out and the pain intensity was also reduced after taking the Compound Danshen dripping pills, so it was not necessary to use so much nitroglycerin. That is the characteristics of Chinese medicine. As mentioned above, if you compare the Danshen with painkiller tablets, or compare compound Danshen Dripping Pills with nitroglycerin, by the only index of relieve pain, in a whole sense it is not the advantage of Chinese medicine. The advantage of Chinese medicine is treating both symptoms and root causes of diseases. If you take Chinese medicine and it works, then you do not need to take painkiller anymore, so the clinical value of Chinese medicine can really be embodied. Our research in the clinic, the promotion and sale of such product in the market should take into account the true characteristics of traditional Chinese medicine.

    Of course, for the other aspects as we mentioned in the morning, requirements for the quality and security control are the same. So it is with a new medicine. Our experts also talked about it.

    As for safety control indicators, we should do more control at the beginning of the medicinal materials.From the seed to the processing process, all the safetyrelated indicators are more controlled as early as possible,because in the subsequent processing, the control depends on the detection on external indicators, but the core of control is to decrease the safety risk at the beginning. We have established a series of quality standards including packaging materials, accessories, solvents, etc.

    For Danshen Capsule, there are release standards and shelf-life standards, which are not exactly the same as those in China. In China, the quality specification integrates the release and shelf-life standards, as China allows companies to establish an internal control standard,which should be applied when the product is released.

    Just now we simply and quickly review our declaration of E01 Danshen Capsule. And we are now doing the registration of E03 combination herbal medicine in the EU, which we found is more complicated than the single component medicine. Next, some concerns on TCM registration to EU.

    You can look at the data first. Basically its approval of single herb prescription medicine is much more than the combination medicine. Why, because we feel that whether it is TUR or WEU, or new, CMC requirements including GMP, etc., are exactly the same. Regulatory bureau in various countries in EU believes that quality of each medicinal material of the combination medicine should be controlled. Of course, there should be DER data from the medicinal material to the extracts, each of which must be quantitatively controlled. And the DER data should be extended into each extract of the preparations.If the compound has multiple extracts, each extract should be controlled accordingly in the preparation. Such a requirement actually leads to a problem, which means that making a botanical medicines is similar to hundreds of pharmaceutical chemicals. It is very strict. However, most of herbal medicines are combination medicines, which are more able to get in the market, at least in the Chinese market. Professor Zhang Junhua said that there were more than 500 herbal products over a hundred million in China, which are mostly combination. Chinese medicine adheres to the principle of monarch and minister, and compatibility. It treats people as a whole, instead of a single symptom. The disease is constantly evolving. For the treatment of diseases, it is necessary to consider that the disease may have different causes, mechanism, and further transformation. Why Chinese medicine can treat both symptom and root causes? Chinese medicine not only controls the beginning of the disease, but also of its end. That is what the principle monarch and minister refer to. Of course, that is my simple understanding.

    This is the second top of Tasly TCM product,Yanxue Qingnao Granules I just mentioned, in which there are 11 medicinal materials of compatibility,completely related to its therapeutic effects. But as far as we know, its material basis is clear, so is the pharmacological effects. Also, the new herb medicines have sufficient clinical data to confirm efficacy, as well as Yangxue Qingnao Granules, treating headache, migraine,chronic cerebral insufficiency (CCCI).

    There is a problem, most of popular herbal medicines are those that can be recognized by its efficacy in the Chinese market, but those medicines have usually no history in the EU for 15 years or in WEU for 10 years. Therefore, there is almost no way to TUR for the proved prescriptions of good efficacy, nor do WEU, for it seems that almost single herb prescription medicine can be approved by WEU. Of course, there is still a new drug application way, but it involves a problem of inputoutput ratio. It is true that R&D cycle of the entire new medicine is very long, which needs a lot of investment. I don't think sponsor will prefer to choose a NDA way in EU for a combination herb medicine, if this, maybe FDA NDA is not a too bad choice. At this point, we have not completely found a particularly suitable path. On the view side from EU to China approval, the situation maybe similar, so I hope that in the future, experts and friends from the European business community will have more exchange and cooperation with us.

    We feel that if it is to put this work clearly in such a market, Chinese medicine products can be rapidly introduced into the shortcut of European program.This is not only beneficial for China to communicate with Europe, but for the world citizen to use medical resources. Those are the goals of every medicine regulatory authority.

    The second concern is the choice of indications. As for the indications, experts in the morning said that there are many requirements for the TUR indication. Patients must use the medicine by himself or herself provided that doctors need not to diagnose, in case the patient used the medicine, it would not delay diseases and other aspects.But TUR indication description focus on symptoms, it cannot state the clinical effects and clinical value detail information, nor instruct patients to take herbal medicine precisely.

    So, although TUR don't require clinical test, we do prefer to have some clinic observation in EU, hoping that when we finish TUR registration in Europe, we can have relevant data of clinical research in EU to support marketing. So, there is a question, for TUR herbal medicine, can the sponsor do clinical observation in EU before or during the TUR application with some clinical research organization of EU, or is there any requirement to begin the clinical observation until the herbal medicine has TUR registration approval? In addition, We have discussed this problem with a medical university in Germany who wants to cooperate with us, they feel that we must get the corresponding (medicine) approval before we can do this. We hope to have a good way to strengthen the research in this area. Also, another question is whether we can delete the statement "The indication is exclusively based on traditional use and not on clinical evidence" in TUR product brochure.

    Additionally, regarding new indictation, we have already talked about the role of Danshen in cardiovascular.We have carried out the preliminary analysis related and have studied it a lot in the field of network pharmacology.This slide demonstrate the mechanism by the integration of Chinese and Western medicine. In the case of Chinese medicine, the mutual involvement of phlegm and stagnation leads to the disease. Therefore, there will be cardiovascular problems in the end. Danshen can play the role of promoting blood circulation and removing blood stasis. Meanwhile, according to the modern pharmacology, Danshen has a clear effect on the obstacles of microcirculation, with clear efficacy. According to the integration of Chinese and western medicine, we believe that Danshen can be used in coronary artery and microvascular disease, because this disease are listed in formal therapeutic guidelines in the EU in 2013, so we plan to apply for a new indication of Danshen Capsule.

    The third concern, we will talk about some problems when we are doing specific development. As there are some shared views in European Pharmacopoeia and Chinese Pharmacopoeia, there may be different quality standards except for the basic principles.

    As for liquorice , the specification limit of glycyrrhizic acid is more than 4% in the EP, and is more than 2% in ChP. Why is that difference? At that time,when the standards were set in Europe, I guess that it was basically wild liquorice. However China could not pick wild liquorice because of environmental protection.

    We detected dozens of liquorice samples, the results show that only wild sample can conform to EP limit.Additionally , there are some other issues, even if for a same thing, the indicators are almost the same in EP and ChP, only some differences in details of test method. So we need to do additional test again by EP, then the cost will rise for a TUR product, but on the other hand, we have to have a series of competitions with other health products, which usually have a low price without so much compliance cost. Can we strengthen the communication between the two sides?There seems no particular channel to have an effective market for TUR product. Some experts said earlier that there is no need for medical insurance, and patients use medicines on their own, so a more suitable way for herbal medicines in EU market is also important to support more and more development and registrtation.

    The fourth concern is about product formulation with extract. Whether it is a single herb prescription, or herbal combination TUR in EU, or NDA for FDA, the finished product formulation can be expressed by the amount of extract directly, no need the amount of herbal substance. China is now also considering how to adopt the formulation with extract. So we can make so more communication and share lots of practices, and can learn much more each other.

    In summary, I mentioned it intermittently that the purpose of TUR is for the market. We hope that the study of clinical observation can be allowed to carry out before registration approval, to clarify the advantages and clinical value, and to instruct usage precisely, also to support marketing development, rather than getting the result by the original literature.

    In terms of sales channels, as TUR can only go through those channels which can not be combined with medical insurance and payment systems. We believe that we should form a way for clinical treatment by the integration of Chinese and Western medicine, to integrate a mode of medical insurance payment which can figure out a valuable clinical pathway to combine the advantages of Chinese medicine with western treatment.

    That is a path we are now exploring in Germany. I hope that everyone here whether from scientific research or from the industry, will explore the characteristics of how traditional Chinese medicine should be used and its true clinical value, by strengthening cooperation. Thank you.

    Host: Dr. Zhang gave us introduction of Danshen Capsules declared by their company and shared their experience in registering in Europe. He specially emphasized some challenges in applying for TUR combination products. I believe that their experience will have great 參考文獻 value for promoting the EU registration in the future. And it can make some help to improve the regulation, the unified policies and communication between China and the EU.

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